The most effective symptomatic treatment of Parkinson""s disease involves the administration of L-xcex2-3,4-dihydroxyphenylalanine (L-DOPA), the immediate precursor of dopamine. Orally administered L-DOPA is predominantly metabolised in the periphery by aromatic L-amino acid decarboxylase (AADC) to dopamine, which can cause serious adverse effects such as emesis, orthostatic hypotension and cardiac arrhythmia. Therefore, L-DOPA is usually administered in combination with a peripheral AADC inhibitor (benserazide or carbidopa). When administered together with such inhibitors, very little dopamine is formed in the periphery, but only a small amount of an oral dose of L-DOPA reaches the brain because a considerable amount of the drug undergoes methylation to, 3-O-methyl-L-DOPA (Mxc3xa4nnistxc3x6, P. A., et al., Progress Drug Research, 39: 291-350, 1992). The duration of the L-DOPA-induced clinical improvement is brief as a result of the short half-life of L-DOPA, which contrasts with the long half-life of 3-O-methyl-L-DOPA. Within a few years after starting L-DOPA therapy with the customary 2 to 4 doses per day, L-DOPA-induced clinical improvement wanes at the end of each dose cycle, producing the xe2x80x9cend-of-dosexe2x80x9d or xe2x80x9cwearing-offxe2x80x9d pattern of motor fluctuations. A close relationship has been described between accumulation of 3-O-methyl-L-DOPA and development of the xe2x80x9cwearing-s offxe2x80x9d phenomenon (Tohgi, H., et al., Neurosci. Letters, 132:19-22, 1992). It has been anticipated that this might result from inhibition of L-DOPA transport at the level of the blood-brain barrier by its O-methylated metabolite (Reches, A., et al., Neurology, 32:887-888, 1982) or simply because there is less L-DOPA available to reach the brain (Nutt, J. G., Fellman, J. H., Clin. Neuropharmacol., 7:35-49, 1984).
In recent years, the development of new inhibitors of the enzyme catechol-O-methyl transferase (COMT) has been accelerated by the hypothesis that inhibition of this enzyme may provide significant clinical improvements in patients afflicted by Parkinson""s disease undergoing treatment with L-DOPA plus a peripheral AADC inhibitor. The rationale for the use of COMT inhibitors is based on their capacity to inhibit the O-methylation of L-DOPA to 3-O-methyl-L-Dopa. COMT inhibition slows elimination of L-DOPA from the plasma by increasing plasma half-life (increases area under the curve [AUC] without altering the time L-DOPA plasma to peak or the maximum concentration). Thus pharmacokinetic alterations may be an advantage over increasing the dose of L-DOPA, which also increases AUC, but additionally raises peak concentrations. In turn, raising peak concentrations relates to adverse effects such as dyskinesia, which occurs immediately when COMT inhibitors are given but can be anticipated by either reducing the dose of L-DOPA or increasing the time intervals between doses. The effects of COMT inhibition also differ from those of controlled-release L-DOPA formulation which slow down absorption and reduce bioavailability. The pharmacokinetic changes induced by COMT inhibition reduce the daily L-DOPA dose by enabling a reduction of each dose or an increase in dose intervals. With repeated doses of L-DOPA every 2-6 h in the presence of COMT inhibition, the mean plasma L-DOPA concentration is raised and the through concentrations are increased proportionally more than the peak concentrations despite a reduction in L-DOPA dose. As would be predicted by the slowed elimination of L-DOPA, the duration of antiparkinsonian action with single doses of L-DOPA is prolonged by COMT inhibition (Nutt, J. G., Lancet, 351:1221-1222, 1998).
The most potent and selective COMT inhibitors found so far are very active and do not interact with other enzymes, receptors, ionic channels or transporters up to very high doses. Some of them were demonstrated to have beneficial effects both in experimental models of parkinsonism and in Parkinson""s disease patients. Other therapeutic applications of these COMT inhibitors have also been put forward, namely in the treatment of depression or anxiety, as gastroprotective drugs and as natriuretic and antihypertensive agents.
The most potent COMT inhibitors thus far reported, 3,4-dihydroxy4xe2x80x2-methyl-5-nitrobenzophenone (tolcapone, Australian Pat. AU-B-69764/87), and (E)-2-cyano-N,N-diethyl-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide (entacapone, German Pat. DE 3740383 A 1) have inhibition constants in the low nM range. Tolcapone differs from entacapone in being a more potent inhibitor of COMT in the periphery and furthermore at penetrating into the brain to inhibit brain COMT as well. It has not been established which of these two inhibitors is more useful in the treatment of Parkinson""s disease. Compounds penetrating the blood-brain barrier may be assumed to be more effective as theoretically they might have additional benefits of decreasing dopamine methylation to 3-methoxytyramine and homovanillic acid. Conversely, central inhibition may be unimportant if the more significant action is to protect L-DOPA from breakdown in the periphery. This distinction may have practical importance, as the use of COMT inhibitors which are excluded from the brain may avoid potential undesired CNS side effects of these agents.
In this respect, it is interesting to underline the lack of antiparkinsonian action of tolcapone when given alone (Hauser, R. A., et al., Mov Disord, 1998, 13, 643-647), and the relatively frequent observations of increased central dopaminergic stimulation, primarily dyskinesia and confusion, in patients taking L-DOPA plus tolcapone (Nuft, J. G., Lancet, 351:1221-1222, 1998). This suggests that the central effects of COMT inhibition are very small when given alone, but when given with L-DOPA the risk of inhibition of brain COMT may be associated with the appearance of symptoms related to increased dopaminergic stimulation which may require cessation of therapy.
Another potential problem with COMT inhibitors concerns their relatively short half-life (tolcapone, 2 h [Dingemanse, J., et al., Clin. Pharmacol. Ther., 57:508-517, 1995]; entacapone, 0.3 h [Keranen, T., et al., Eur. J. Clin. Pharmacol., 46:151-157, 1994]). To circumvent this problem both tolcapone and entacapone are recommended to be administered as frequently as 3 times a day; because the half-life of entacapone is considerably shorter than that of tolcapone, the recommended dose for entacapone is twice that for tolcapone.
As previously mentioned, the 3,4-dihydroxy-5-nitrophenyl group was identified as an active pharmacophore and it was simultaneously discovered that the presence of a carbonyl group (e.g. in tolcapone ) or enone group (e.g. in entacapone) conjugated to the pharmacophore of the molecule generally enhances inhibition of the COMT catalysed transfer of the methyl group from the S-adenosyl-L-methionine coenzyme to a substrate containing a catechol functional group. Among many tested compounds bearing a 3,4-dihydroxy-5-nitrobenzoyl group, the corresponding benzophenones were recognized as the most potent COMT inhibitors with ED50 less than 1 mg/kg (rat, p.o.) (Borgulya J. et al., Helvetica Chimica Acta 72, 952-968, 1989).
Formation of homologues of known biologically active compounds as potentially improved drugs is a well known principle and is used mainly for optimization of activity of structurally nonspecific drugs or for achieving changes in predominant biological action in structurally specific drugs (Korolkovas A. Essentials of Medicinal Chemistry, p. 76, 1988 by J. Wiley and Sons, Inc.). On the other hand, homologation is not generally used nor expected to influence predictably the half-life of a compound.
We have surprisingly proven that the next higher homologue of 3,4-dihydroxy-5-nitrobenzophenone i.e. the compound with one more methylene group between the substituted benzoyl group and phenyl group is endowed with selective COMT inhibition of long duration and that this effect is unique in a series of the higher homologues.
The invention relates to substituted 2-phenyl-1-(3,4-dihydroxy-5-nitrophenyl)-1-ethanones of formula I 
where R1 and R2 are hydrogens or groups hydrolysable under physiological conditions, the same or different, and signify optionally substituted lower alkanoyl or aroyl, optionally substituted lower alkyl or arylsulphonyl or optionally substituted lower alkylcarbamoyl, or taken together signify a lower alkylidene or cycloalkylidene group; R3, R4 and R5 are the same or different and signify hydrogen, optionally substituted saturated or partially unsaturated lower hydrocarbon residue, hydroxyl, optionally substituted lower alkoxy or aryloxy group, optionally substituted aryl, optionally substituted alkanoyl or aroyl group, lower alkanoylamino group, lower dialkanoylamino group, carboxyl, optionally substituted lower alkyloxycarbonyl or aryloxycarbonyl group, optionally substituted carbamoyl, halogen, nitro, amino, lower alkylamino or lower dialkylamino or cyano group, or taken together signify aliphatic or heteroaliphatic rings or aromatic or heteroaromatic rings, and pharmaceutical acceptable salts thereof; to the use of the compounds for prevention or treatment of certain pathological states in humans and to the preparation of pharmaceutical compositions containing them.
The term xe2x80x9clowerxe2x80x9d denotes residues with a maximum of 8, preferentially a maximum of 4 carbon atoms. The term xe2x80x9calkylxe2x80x9d taken alone or in combination with terms such as xe2x80x9calkanoyl, alkoxycarbonyl, alkylidene, cycloalkylidene, alkoxycarbonyloxy, alkylaminoxe2x80x9d denotes straight-chain or branched saturated hydrocarbon residues. The term halogen denotes fluorine, chlorine, bromine, and iodine. The term xe2x80x9carylxe2x80x9d denotes a carbocyclic aromatic group, preferably mono- or bicyclic groups.
For the preparation of pharmaceutical compositions of compounds of formula I, inert pharmaceutically acceptable carriers are admixed with the active compounds. The pharmaceutically acceptable carriers may be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules and capsules. A solid carrier can be one or more substances which may also act as diluents, flavouring agents, solubilizers, lubricants, suspending agents, binders or tablet disintegrating agents; it may also be an encapsulating material.
Preferably, the pharmaceutical preparation is in unit dosage form, e.g. packaged preparation, the package containing discrete quantities of preparation such as packeted tablets, capsules and powders in vials or ampules.
The dosages may be varied depending on the requirement of the patient, the severity of the disease and the particular compound being employed. For convenience, the total daily dosage may be divided and administered in portions throughout the day. Determination of the proper dosage for a particular situation is within the skill of those in the medical art.